B cell antibody responses are triggered by the binding of antigen to the clonally distributed B cell antigen receptors (BCRs). Over the last several years a great deal has been learned about the biochemistry of the complex signal cascades triggered by BCR antigen engagement. Signaling is initiated by phosphorylation of the BCR by a membrane associated member of the Src family kinases, Lyn. At present, the initiating event in B cell activation that brings the antigen bound BCR into contact with Lyn is not known. Over the last year we have applied the new technology of FRET imaging that allows us to view the interactions of proteins and lipids in living cells, to better characterize the earliest events in antigen-driven BCR signaling, namely, the oligomerization of the receptor and its association with sphingolipid- and cholesterol-rich membrane microdomains termed lipid rafts. Using quantitative FRET imaging we showed that the BCR is a monomer of the surface of resting cells and that multivalent antigen binding results in the simultaneous phosphorylation of the receptor?s cytoplasmic domains, a change in the BCR?s cytoplasmic domains from a clustered to an open form and the rapid yet transient association with lipids that compose lipid rafts. These events precede the activation of downstream signaling events and require the continuous activity of Src-family kinases but not the binding of Syk. Thus, the initiation of BCR signaling is a remarkably dynamic process accompanied by reversible conformation changes and raft lipid associations induced by Src-family kinase activity. Efforts are under way to introduce appropriate FRET donor and acceptor pairs into transgenic mice to allow us to image signaling events in normal B cell subsets. Efforts have also been made to image the BCR and associated signaling components at single molecule level using total internal reflection fluorescence (TIRF) microscopy.